Folic Acid Dosing with Methotrexate 12.5 mg Weekly
Prescribe at least 5 mg of folic acid per week for any patient starting methotrexate 12.5 mg weekly. 1
Recommended Dosing Regimens
The evidence supports multiple acceptable approaches, all providing at least 5 mg weekly:
- 5 mg once weekly (taken the day after methotrexate administration to avoid competitive cellular uptake) 1, 2
- 1 mg daily (taken every day except the day methotrexate is administered) 1, 3, 4
- 5 mg daily (for patients with severe disease or pre-existing folate depletion) 1
Why This Dosing Matters
Folic acid supplementation at ≥5 mg weekly is strongly recommended (Grade A evidence) and reduces methotrexate toxicity without compromising efficacy. 1
The benefits are substantial and well-documented:
- 26% relative risk reduction (9% absolute) in gastrointestinal side effects including nausea, vomiting, and abdominal pain 5
- 77% relative risk reduction (16% absolute) in abnormal liver transaminase elevation 5
- 61% relative risk reduction (15% absolute) in treatment discontinuation for any reason 5
- Protective effect against hepatotoxicity and mucosal side effects 1
- Reduces cardiovascular risk by offsetting methotrexate-induced hyperhomocysteinemia 2
Timing Considerations
Do not administer folic acid on the same day as methotrexate. 1, 6
Folic acid may theoretically compete with methotrexate for cellular uptake when given simultaneously, potentially reducing efficacy. 1 The most common practical approach is to give folic acid the morning after methotrexate administration if using weekly dosing, or daily except on methotrexate day if using daily dosing. 2, 1
Folic Acid vs. Folinic Acid
Use folic acid rather than folinic acid (leucovorin). 1
Meta-analysis shows folinic acid offers no advantages over folic acid for routine supplementation, and folinic acid is significantly more expensive. 1 Reserve folinic acid (leucovorin 10 mg/m²) only for methotrexate overdose or severe hematologic toxicity requiring immediate antidote therapy. 1
Dose Adjustment Considerations
If your patient develops intolerable side effects despite standard folic acid supplementation:
- First: Increase folic acid to 5 mg daily (except methotrexate day) 1
- Second: Consider split-dose methotrexate (divided over 24 hours at 12-hour intervals) 6
- Third: Switch to subcutaneous methotrexate for better bioavailability and reduced GI toxicity 6
Common Pitfalls to Avoid
Do not withhold folic acid thinking it will improve methotrexate efficacy. Multiple high-quality studies confirm that folic acid supplementation does not reduce methotrexate's therapeutic effect on disease activity parameters. 5, 7, 8 In fact, one study showed patients on folate supplementation tolerated slightly higher methotrexate doses (18 mg/week vs. 14.5 mg/week), achieving similar disease control. 7
Do not use inadequate doses. The multinational rheumatology guidelines explicitly state "at least 5 mg per week" as the minimum threshold. 1 Lower doses may not provide adequate protection against toxicity.